POS0117 REMIBRUTINIB SPECIFICALLY DOWNREGULATES MARKERS OF MEMORY B CELL SUBSETS IN SJÖGREN’S PATIENTS (SJS) IN THE LOUISSE PHASE 2 CLINICAL TRIAL
Authors: A. Grioni, A. Santos Da Costa, E. Ferrero, V. De Luca, R. Hillenbrand, A. Da Costa, B. Cenni, M. Kaul, T. Dörner, R. Siegel
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Remibrutinib is a selective, covalent and potent inhibitor of Bruton's tyrosine kinase (BTK) in development for several autoimmune and auto-allergic indications showing promising clinical safety and efficacy (Kaul et al 2021, Maurer et al 2022). Sjögren's (SjS) is a chronic autoimmune disorder characterized by dryness in the eyes and mouth, fatigue, joint pain, and reduced quality of life (Mariette et al 2018). Remibrutinib may be particularly promising for the treatment of SjS due to its ability to target underlying B cell abnormalities and showed promising efficacy in a Ph2 SjS trial (Dörner et al 2022). <h3>Objectives</h3> The aim of this exploratory biomarker study within the LOUiSSe trial was to identify protein and transcript signatures in the blood of patients with active SjS that are associated with remibrutinib treatment. <h3>Methods</h3> We conducted the LOUiSSe Ph2 clinical trial (NCT04035668) to evaluate the safety and efficacy of remibrutinib in patients with moderate to severe SjS. The study design was a randomized, double-blind, placebo-controlled, multi-center trial. Blood samples were collected at baseline and 24 weeks after treatment began. Protein profiles were generated using a Multiplex 7K aptamer profiling, and transcriptomics analysis was performed on RNA extracted from whole blood. By comparing the treatment and the placebo groups over time using multivariate linear regression models, we identified proteins and genes that were differentially modulated by remibrutinib. The gene signature identified by Yao et al (2009) was used as a reference for the interferon signature. <h3>Results</h3> We observed a consistent downregulation of 35 proteins associated with B cell activity, including CD23, FCRL1, FAIM3, and FCRL4, in all treatment groups receiving remibrutinib compared to the placebo group after 24 weeks of treatment. These modulated proteins are involved in multiple pathways related to B-cell activation and function, including B-cell receptor signaling, Fc receptor signaling, and platelet activation. Whole blood bulk mRNA sequencing revealed that the remibrutinib group showed a significant downregulation of a 34-gene signature, most of which are known to be important for B-cell activation and immunoglobulin production. The top two most significantly downregulated genes, FCRL5 and SOX5, were previously identified as being highly enriched in a circulating tissue-like memory B-cell subset. This observation is also corroborated by the proteomics profiling analysis, where FCRL4 known to co-localize in the same memory B-cell subset (Verstappen et al 2020, Götz et al 2008), was heavily decreased by the treatment. Despite the specific and strong effects on B-cells, estimation of cell type proportions using RNA-seq revealed no significant changes, suggesting that remibrutinib does not affect the overall B-cell numbers and the relative proportions of its major subsets, like plasma cells, naïve and memory B-cells. Results from both proteomics and transcriptomics profiling suggest that remibrutinib treatment does not modulate the interferon signature. <h3>Conclusion</h3> Our analysis of serum proteins and whole blood transcripts showed that remibrutinib treatment was associated with a significant downregulation of proteins and genes enriched in FcRL4+ B cells, a subset of tissue-resident memory B cells that are expanded in inflamed tissues and found in the salivary glands of SjS patients. These findings suggest that remibrutinib may have a particularly strong inhibitory effect on this subset. Additionally, many genes and proteins involved in B-cell activation, differentiation, and maturation were also downregulated, indicating that remibrutinib has a potent effect on multiple B-cell pathways. <h3>References</h3> [1]Kaul et al, Clin Transl Sci. 2021 [2]Mariette X, et al. N Engl J Med. 2018; [3]Maurer, M. et al. 2022 [4]Dörner T, et al, Arthritis Rheumatol. 2022 [5]Verstappen GM, et al. J of Autoimmunity 2020 [6]Götz R.A. Ehrhardt, et al. J Exp Med. 2008 [7]Yihong Yao et al, Americ Coll Reum 2018 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Andrea Grioni Shareholder of: Novartis, Employee of: Novartis, Aida Santos da Costa Shareholder of: Novartis, Employee of: Novartis, Enrico Ferrero Shareholder of: Novartis, Employee of: Novartis, Valeria De Luca Shareholder of: Novartis, Employee of: Novartis, Rainer Hillenbrand Shareholder of: Novartis, Employee of: Novartis, Andre da Costa Shareholder of: Novartis, Employee of: Novartis, Bruno Cenni Shareholder of: Novartis, Employee of: Novartis, Martin Kaul Shareholder of: Novartis, Employee of: Novartis, Thomas Dörner Consultant of: study support and honoraria for scientific advice: Novartis, Eli Lilly, EMD, BMS; Janssen; AbbVie, Roche/GNE, Richard Siegel Shareholder of: Novartis, Employee of: Novartis.